Chronic heart failure alters orexin and melanin concentrating hormone but not corticotrophin releasing hormone-related gene expression in the brain of male Lewis rats

• Hypothalamic gene expression of both orexin and melanin concentrating-hormone are significantly altered by heart failure.
• Gene expression for orexin receptor type 2 is significantly down-regulated in the dorsal pons and amygdala by heart failure.
• Changes in orexin and orexin receptor type 2 expression are correlated with changes in cardiac function.
• The brain's orexin system may play an important role in the pathophysiology of heart failure.

ObjectiveThe aim of this study was to investigate the effect of chronic heart failure (HF; 16 weeks post left coronary artery ligation) on the brain's orexin (ORX) and related neuropeptide systems.MethodsIndicators of cardiac function, including the percent fractional shortening (%FS) left ventricular posterior wall shortening velocity (LVPWSV) were assessed via echocardiography at 16 weeks post myocardial infarction or sham treatment in male Lewis rats (n = 5/group). Changes in gene expression in HF versus control (CON) groups were quantified by real-time PCR in the hypothalamus, amygdala and dorsal pons.ResultsHF significantly reduced both the %FS and LVPWSV when compared to CON animals (P < 0.02). In the hypothalamus ORX gene expression was significantly reduced in HF and correlated with changes in cardiac function when compared to CON (P < 0.02). No significant changes in hypothalamic ORX receptor (type 1 or type 2) gene expression were identified. Alternatively hypothalamic melanin concentrating hormone (MCH) gene expression was significantly upregulated in HF animals and negatively correlated with LVPWSV (P < 0.006). In both the amygdala and dorsal pons ORX type 2 receptor expression was significantly down-regulated in HF compared to CON. ORX receptor type 1, CRH and CRH type 1 and type 2 receptor expressions were unchanged by HF in all brain regions analyzed.ConclusionThese observations support previous work demonstrating that cardiovascular disease modulates the ORX system and identify that in the case of chronic HF the ORX system is altered in parallel with changes in MCH expression but independent of any significant changes in the central CRH system. This raises the new possibility that ORX and MCH systems may play an important role in the pathophysiology of HF.